Delirium, or acute confusional state, is a common, costly, life-threatening, and potentially preventable problem for older persons. Despite its clinical and health policy implications, the epidemiology and long-term outcomes of delirium remain poorly understood. Delirium is conceptualized as acute brain failure, which like heart failure has multiple causes but independently leads to poor outcomes. This Program Project seeks to elucidate novel risk markers (including biomarkers, neuroimaging and reserve markers) and to examine the contribution of delirium to long-term cognitive and functional decline. Importantly, this Program Project will utilize innovative interdisciplinary approaches that will facilitate the translation of findings from the laboratory to the hospital bedside and the community. Four Projects are proposed addressing several interlocked hypotheses and cross-linking aims, and exploring: the long-term cognitive and functional outcomes of delirium (Project 1); plasma biomarkers for delirium and long-term decline (Project 2); neuroimaging markers for delirium and long-term decline (Project 3); and the role of cognitive and brain reserve in delirium and long-term decline (Project 4). All Projects involve a prospective cohort of 500 older patients scheduled for major surgery who are free of dementia, and who will be enrolled in the community prior to surgery and followed prospectively for 18-36 months from their initial hospitalization with serial evaluations for neuropsychological and functional outcomes. Thus, this work will be unique in characterizing the baseline status of patients prior to the index surgery and delirium onset. The work of the 4 Projects will be supported by 3 Cores: the Administrative Core (Core A), the Epidemiology Core (Core B), and the Data Management and Statistical Analysis Core (Core C). Core A will provide the leadership and organizational structure to ensure integration, efficiency, and productivity. Core B will assemble, maintain, and follow the prospective cohort for the Projects. Core C will provide data management and statistical analysis for all Projects and Cores. This Project brings together an extremely strong, committed, and experienced team of interdisciplinary investigators within a highly supportive research environment. Moreover, the Project holds substantial promise to elucidate the contribution of delirium to long-term cognitive and functional decline, to identify novel risk markers, and to provide an innovative conceptualization of delirium as a potentially reversible contributor to dementia, laying the groundwork for future intervention studies to address this important area.